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BioMed Central
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Journal of NeuroEngineering and
Rehabilitation
Open Access
Review
Using non-invasive brain stimulation to augment motor
training-induced plasticity
Nadia Bolognini
1,2,3
, Alvaro Pascual-Leone
1,3
and Felipe Fregni*
1
Address:
1
Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA,
2
Department of Psychology, University of Milano Bicocca, Milano, Italy and
3
Institut Guttmann de Neurorehabilitacio, Universitat Autonoma de
Barcelona, Barcelona, Spain
Email: Nadia Bolognini - ; Alvaro Pascual-Leone - ;
Felipe Fregni* -
* Corresponding author
Abstract
Therapies for motor recovery after stroke or traumatic brain injury are still not satisfactory. To
date the best approach seems to be the intensive physical therapy. However the results are limited
and functional gains are often minimal. The goal of motor training is to minimize functional disability
and optimize functional motor recovery. This is thought to be achieved by modulation of plastic

changes in the brain. Therefore, adjunct interventions that can augment the response of the motor
system to the behavioural training might be useful to enhance the therapy-induced recovery in
neurological populations. In this context, noninvasive brain stimulation appears to be an interesting
option as an add-on intervention to standard physical therapies. Two non-invasive methods of
inducing electrical currents into the brain have proved to be promising for inducing long-lasting
plastic changes in motor systems: transcranial magnetic stimulation (TMS) and transcranial direct
current stimulation (tDCS). These techniques represent powerful methods for priming cortical
excitability for a subsequent motor task, demand, or stimulation. Thus, their mutual use can
optimize the plastic changes induced by motor practice, leading to more remarkable and outlasting
clinical gains in rehabilitation. In this review we discuss how these techniques can enhance the
effects of a behavioural intervention and the clinical evidence to date.
Introduction
Motor impairments following stroke or traumatic brain
injury (TBI) are the leading cause of disability in adults.
More than 69% of all stroke survivors experience lasting
functional motor impairments in the upper limbs and
approximately 56% continue to complain of marked
hemiparesis as long as 5 years post-stroke [1-5]. Such
losses in function can severely impact quality of life and
the functional independence in numerous activities of
daily living [4,5]. Similarly, after TBI, fine and gross motor
deficits are frequently observed. Complementary impair-
ments such as ataxia, movement disorders and vestibular
impairments, can also potentially affect motor function-
ing in TBI. Moreover, other factors such as multiple
trauma, resulting in musculo-skeletal and peripheral nerv-
ous system injury, also complicate the recovery of motor
functions in these patients [6].
Although some degree of recovery may occur spontane-
ously, there is strong evidence that intensive practice is

essential in order to substantially promote motor recovery
[7-9]. As shown by several neurobehavioral discoveries in
Published: 17 March 2009
Journal of NeuroEngineering and Rehabilitation 2009, 6:8 doi:10.1186/1743-0003-6-8
Received: 17 November 2008
Accepted: 17 March 2009
This article is available from: />© 2009 Bolognini et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( />),
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Journal of NeuroEngineering and Rehabilitation 2009, 6:8 />Page 2 of 13
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animals and humans, such experience-dependent change
can occur at multiple levels of the central nervous system,
from the molecular, to the synaptic level of cortical maps
and large-scale neural networks [10,11].
Standard motor therapies involve different approaches
aimed at improving motor functions by minimising
impairment or developing suitable adaptation strategies.
For instance, neurofacilitation techniques are aimed at
retraining motor control by promoting normal (recruit-
ment of paretic muscles) while discouraging abnormal
movement or muscle tone. Different facilitation
approaches have been developed, including cutaneous/
proprioceptive, weight bearing, proximal pre-innervation,
and contralateral pre-innervation [12]. Task-specific train-
ing is aimed at improving skill in performing selected
movement or functional tasks: examples of this type of
treatment are index finger tracking [13] or the combina-
tion of task-specific motor training with the inhibition of
ipsilesional sensorimotor cortex representation of the

paretic upper arm by local anaesthesia [14]. Finally, task-
oriented training aimed at retraining functional tasks by
taking into account the interplay of different systems is
another possible approach. For example, constrained-
induced movement therapy (CIMT) combines intensive
physical practice using the affected upper limb with
restricted use of the unaffected upper limb in order to pre-
vent its habitual compensatory utilization [15]. Bilateral
arm training is instead based on the phenomenon of
interlimb coupling, in which the movement patterns of
the arms are similar when moving simultaneously
[16,17]. Ongoing studies indicate that even mere action
observation, activating the same cortical motor areas that
are involved in the performance of the observed actions
(i.e. action observation/execution matching system) can
lead to a reorganization of the motor system resulting in
an improvement of motor functions [18,19]. Other treat-
ments have focused on the use of robotics [20,21], EMG-
triggered stimulation [22], and motor imagery [23] (see
for a review [24]).
Although there is little doubt that behavioural motor ther-
apy clearly plays a role in promoting contra- and ipsi-
lesional plastic changes after stroke, the functional out-
comes are often of limited practical significance and after
completing standard rehabilitation approximately 50–
60% of patients still exhibit some degree of motor impair-
ment and require at least partial assistance in activities of
day living [24,25]. Similarly, the efficacy of the majority of
standard motor interventions for promoting recovery
after TBI is supported by rather limited evidence [6].

Therefore, investigation of other approaches to promote
the recovery of motor impairments is essential. In this
context, noninvasive brain stimulation (NIBS) appears to
be an interesting option [26]. Transcranial Magnetic Stim-
ulation (TMS) is delivered to the brain by passing a strong
brief electrical current through an insulated wire coil
placed on the skull. Current generates a transient mag-
netic field, which in turn, if the coil is held over the sub-
jects head, induces a secondary current in the brain that is
capable of depolarising neurons. Depending on the fre-
quency, duration of the stimulation, the shape of the coil
and the strength of the magnetic field, TMS can activate or
suppress activity in cortical regions [27]. Another method
of non-invasive brain stimulation is transcranial Direct
Current Stimulation (tDCS) which delivers weak polariz-
ing direct currents to the cortex via two electrodes placed
on the scalp: an active electrode is placed on the site over-
lying the cortical target, and a reference electrode is usu-
ally placed over the contralateral supraorbital area or in a
non-cephalic region. tDCS acts by inducing sustained
changes in neural cell membrane potential: cathodal
tDCS leads to brain hyperpolarization (inhibition),
whereas anodal results in brain depolarization (excita-
tion) [28,29]. Differences between tDCS and TMS include
presumed mechanisms of action, with TMS acting as
neuro-stimulator and tDCS as neuro-modulator. Moreo-
ver, TMS has better spatial and temporal resolution, TMS
protocols are better established, but tDCS has the advan-
tage to be easier to use in double-blind or sham-control-
led studies [30] and easier to apply concurrently with

behavioural tasks (for discussion of these methods, simi-
larities and differences, see the review by Wagner et al.
[31]). Despite their differences, both TMS and tDCS can
induce long-term after-effects on cortical excitability that
may translate into behavioural impacts that can last for
months [32-35]. These long-term after-effects are believed
to engage mechanisms of neural plasticity, rendering
these techniques ideally suited to promote motor recovery
particularly when combined with suitable behavioural
interventions (for review, see [26,36,37]).
To date, two approaches have been tested. They are based
on a model of interhemispheric rivalry between motor
areas in the damaged and undamaged (intact) hemi-
spheres. In essence, the model proposes that motor defi-
cits are due to reduced output from the damaged
hemisphere and excess inhibition of the damaged hemi-
sphere from the intact hemisphere [26,38]. Thus,
improvement may be possible by either up-regulating
excitability of the lesioned motor cortex or down-regulat-
ing excitability in the intact motor cortex [26]. Enhance-
ment of excitability can be achieved with either high
frequency rTMS and anodal-tDCS. Suppression of excita-
bility can be accomplished with either low-frequency
rTMS and cathodal-tDCS. A growing body of evidence
from small clinical trials has demonstrated the efficacy of
both approaches to induce considerable changes on corti-
cal excitability, which often correlate with relevant clinical
gains in motor functions. However, most studies to date
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have examined the effects of NIBS without coupling it
with any specific behavioural, physical or occupational
therapy, and the functional benefits are often limited,
inducing about 10–20% functional improvement in some
single-session and longer-term therapeutic trials [37]. This
is probably a suboptimal approach, as NIBS activates neu-
ral circuits in a non-specific way. Therefore given that
NIBS and motor training are thought to share synergistic
impacts on synaptic and network plasticity an emerging
field of research is focusing on the possibility of coupling
both therapies in order to achieve additive practical
impact. The underlying principle of this approach is that
practice of a motor task may be more effective at using the
(surviving) neural mechanisms sub-serving training-
dependent plastic changes if pertinent areas of the cortex
are facilitated [38]. In addition, motor training can guide
the activation of specific neural networks associated with
the desired behavior. Considering for instance that many
of the spontaneous plastic changes induced by a stroke,
including phenomena of hyperexcitability, diminish after
a few months [39-41], the therapeutic window of poten-
tial plastic changes for motor recovery seems to be lim-
ited. NIBS might be helpful to prolong this therapeutic
window thus offering a greater opportunity for suitable
physical and occupational therapies to promote func-
tional recovery. Although preliminary, there is some
recent encouraging evidence supporting the clinical valid-
ity of this approach.
Mechanisms of NIBS to induce neuroplasticity
After a stroke affecting the motor cortex, cortical excitabil-

ity is generally decreased in the affected primary motor
cortex relative to the unaffected motor cortex. This might
result from a shift in interhemispheric interactions, with
increased transcallosal inhibition from the intact to the
damaged motor cortex [41,42]. In this scenario, TMS and
tDCS applied over the intact hemisphere allow safe corti-
cal stimulation in humans in order to promote restoration
of activity across bihemispheric neural networks and guid-
ance towards more-adaptive plasticity [26,43].
TMS uses a rapidly changing magnetic field to induce elec-
tric currents via electromagnetic induction. A very brief
high-intensity electric current is passed through a wire coil
held over the scalp, this generates a magnetic field pulse
which passes relatively unimpeded through the layers of
tissue and bone and reaches the brain where secondary
currents are induced. These secondary currents are
induced in a plane parallel to the plane of the stimulation
coil, which typically is held tangentially to the scalp, over
the subject's head. Current direction and electric field dis-
tribution depend on output pulse shape of the stimulator
and coil geometry respectively. The secondary current can
be sufficient to depolarize cortical neurons, directly at
their axon hillock or indirectly via depolarization of
interneurons. Exactly which neural elements are activated
by TMS and the mechanisms of neuronal stimulation
remains unclear and might be variable across different
brain areas and different subjects [27]. We know that
when TMS is delivered over the primary motor cortex with
adequate intensity, it induces efferent volleys along the
corticospinal pathway [44]. Crucially, the therapeutic rel-

evance of this technique is due to the long-term effects
that occur after repeated stimulation. TMS delivered in a
repetitive mode (rTMS) can indeed modulate cortical
excitability beyond the duration of the rTMS trains them-
selves [45]. Depending on rTMS parameters, long lasting
suppression or facilitation of cortical excitability can be
induced: low-frequency rTMS (≤ 1 Hz) usually results in
decreased cortical excitability [46], whereas at higher fre-
quencies (>1 Hz) cortical excitability is usually increased
[45]. It should however be noted, that this is an average
effect across individuals, and yet there is substantial inter-
individual variability as well as intra-individual variability
depending on the timing and exact location of stimula-
tion [47,48].
In promoting stroke recovery, both, high frequency rTMS
and low frequency rTMS have been tested and appear
promising. For instance, Takeuchi et al. [49] and Fregni et
al. [32] applied low-frequency rTMS to suppress activity in
the contralesional (undamaged) hemisphere in chronic
stroke patients: this suppressive protocol proved to be
effective in reducing the transcallosal inhibition from the
intact to the affected motor cortex [49] and increasing
excitability of the lesioned motor cortex [32]. On the
other hand, up-regulating the excitability of the lesioned
M1 can also be successful. Talelli et al. (2007) reported
that a single session of excitatory intermitted theta burst
stimulation (TBS), consisting in delivering 3 pulses at 50
Hz, repeated at a rate of 5 Hz, increased MEP amplitude
on the stroke side, with additional transiently improve-
ment of motor behaviour [50]. By contrast, in the same

study, continuous TBS of the unaffected motor cortex,
which like low frequency rTMS suppresses excitability, did
not change motor behaviour or the electrophysiology of
the paretic hands [50]. Di Lazzaro et al (2008) obtained
slightly different results. They showed that in acute stroke
patients both intermittent TBS over the stroke hemisphere
and continuous TBS over the intact hemisphere enhanced
the excitability of the lesioned motor cortex and resulted
in a functional benefit [51].
Despite these promising results, some limitations of TMS
need to be noted. Critically, after stroke, there is a change
in the local anatomy and the lesion evolves in time to for-
mation of scar tissue and, particularly in the case of corti-
cal damage, larger cerebrospinal fluid spaces. Because the
conductance of cerebrospinal fluid (CSF) is 4 to 10 times
higher than that of brain tissue, scar formation and larger
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CSF spaces modify the geometry and magnitude of the
electric field induced by rTMS, and stimulation of the
lesioned hemisphere can become difficult to predict
unless careful modelling is done [52].
The mechanisms underlying long-term effects of TMS are
incompletely understood, but they could be analogous to
long-term potentiation (LTP) or depression (LTD) seen in
the hippocampus after repeated activation of synaptic
pathways [53-55]). In addition, modulation of neuro-
transmitter levels seems to be a contributing factor. The
neurotransmitter systems involved include the inhibitory
GABAergic system [56-58] as well as the excitatory gluta-

matergic system with activation of NMDA receptors [57].
TMS may result in changes in endogenous neurotransmit-
ters (GABA and glutamate) and neuromodulators (DA,
NE, 5-HT, ACh) which play a pivotal role in the regulation
of the neuronal activity in the cerebral cortex (for review,
[59]). A focal increase of dopamine in the striatum was
indeed demonstrated in healthy human after sub-thresh-
old 10 Hz rTMS applied to the ipsilateral primary motor
cortex [60] or dorsolateral prefrontal cortex [61].
Another candidate mechanism by which rTMS may exert
persistent effects is through gene induction. Actually,
rTMS can modulate the expression of immediate early
genes [62-64]. A single rTMS train increased c-fos mRNA
in the paraventricular nucleus of the thalamus and,
although to a lesser extent, in the frontal and cingulate
cortices [64]. A longer treatment protocol (up to 14 daily
sessions) could even induce an increase in c-fos mRNA in
the parietal cortex of rodents [63] and an enhancement of
BDNF mRNA in the hippocampus, the parietal and piri-
form cortices [65]. As suggested, BDNF is a neurotrophic
factor that is critically linked to the neuroplastic changes
[66] and might serve to index neuroplastic effects induced
by rTMS [67].
The other main method of NIBS, tDCS, is a form of brain
polarization that uses prolonged low-intensity electric
current (1–2 mA) delivered to two large electrodes (usu-
ally 5 × 7 cm or 5 × 5 cm) to the scalp. To stimulate the
primary motor cortex, usually one electrode is placed on
the scalp over M1 and the other on the contralateral
supraorbital area [68]. Alternatively, the reference elec-

trode can be placed on the shoulder or another extra-cra-
nial location. Reminiscent of the effects of repetitive TMS,
tDCS can up- or down-regulate neural activity in the stim-
ulated regions. Increased excitability of the underlying
neurons occurs with anodal stimulation, while decreased
excitability is seen after cathodal stimulation. With only
13 minutes of tDCS stimulation, effects on neural excita-
bility outlasts the period of stimulation by up to 90 min-
utes [69]. In fact, the after-effects of tDCS appear greater
than those induced by synchronous rTMS [68,70]. How-
ever, TBS or other, more sophisticated, asynchronous
rTMS trains may significantly enhance and prolong the
modulatory effects.
Again reminiscent of the effects of rTMS, tDCS-induced
changes in cortical excitability are associated with changes
in the excitability of inhibitory and facilitatory intracorti-
cal circuits: whereas anodal tDCS results in decreased
intracortical inhibition and increased intracortical facilita-
tion, cathodal stimulation induces opposite effects. In
patients with chronic strokes, either anodal tDCS deliv-
ered to the lesioned M1 or cathodal tDCS delivered to the
contralesional hemisphere can result in an improvement
in motor functions [71-73].
tDCS does not stimulate axons and cause them to dis-
charge action potentials, as TMS does. Rather, it most
likely targets neuronal signalling by manipulating ion
channels or by shifting electrical gradients which influ-
ence the electrical balance of ions inside and outside of
the neural membrane; thus modulating the resting mem-
brane threshold. Apart from membrane potential

changes, chemical neurotransmission, either pre- or post-
synaptically, may play a role in tDCS effects [74]. Some
studies have aimed to clarify the cellular mechanisms of
tDCS over the motor cortex [29,74]. For instance, the
effects of the sodium channel blocker carbamazepine, the
calcium channel blocker flunarizine and the NMDA-
receptor antagonist dextromethorphane on tDCS-elicited
motor cortex excitability changes were tested in healthy
human subjects. Carbamazepine selectively eliminated
the excitability enhancement induced by anodal stimula-
tion during and after tDCS. Flunarizine resulted in similar
changes. Antagonizing NMDA receptors did not alter cur-
rent-generated excitability changes during stimulation,
but prevented the formation of after-effects independent
of their direction. Therefore, authors concluded that corti-
cal excitability shifts induced during tDCS in humans
appear to depend on membrane polarization, thus, mod-
ulating the conductance of sodium and calcium channels.
In addition, the after-effects seem to be NMDA-receptor
dependent. Recently, it was demonstrated that d-cycloser-
ine, a partial NMDA-agonist, selectively potentiates the
duration of motor cortical excitability enhancements
induced by anodal tDCS [75]. Additionally, it was also
suggested that the after-effects of cathodal tDCS include
nonsynaptic mechanisms based on changes in neuronal
membrane function [76]. Long term effects induced by
tDCS may include built-up of new synapses, with mecha-
nism of LTP and LTD critically involved. The glutamater-
gic system, in particular NMDA receptors [77], seems to be
necessary for induction and maintenance of neuroplastic

after-effect excitability enhancement and reduction
induced by tDCS [74].
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Mechanisms of action of motor training in inducing plastic
changes
After brain damage, there is substantial recovery with
clearly delineated dynamics, resulting in a faster recovery
in the acute and subacute stages, gradually levelling off as
time progresses. In addition activity-dependent long-term
modification of synaptic efficacy is associated with infor-
mation storage in neural networks [78]. In fact, Neural
plasticity changes evolve from the Hebbian synapse rule
that states that individual synaptic junctions respond to
activity (use) and inactivity (disuse) [79].
Motor training can promote plastic changes in injured
motor networks even in a chronic stage of illness. How-
ever, simple interventions such as repetitive movement
practice fail to induce profound plastic changes [80]. It
appears that skill learning must be present to promote
cortical plasticity [81]. In fact, most of the recovery of
function after a stroke may represent actual relearning of
the skills with the injured brain. Recovery mediated by
training, like learning in healthy subjects, is usually task-
specific and it differs from processes involved in compen-
sation: whereas recovery of motor functions requires the
recruitment of brain areas to generate commands to the
same muscles as were used before the injury, compensa-
tion is instead based on the use of alternative muscles to
accomplish the task goal [82]. Motor learning will lead

first to strengthening of existing neural pathways, and sec-
ond, to new functional or structural changes and thus
expression of neuroplasticity [8].
The main mechanism underlying this relearning process
after stroke involves shifts of distributed contributions
across a specific neural network. Investigations in adult
animals have revealed that motor learning can promote a
plastic reorganization of motor maps in M1 with the rep-
resentations of specific movements used to perform the
motor task selectively expanding in the motor cortex at
the expense of other areas not used for forelimb represen-
tations [10]. Similar results have been obtained in
humans. For instance, the acquisition of new fine motor
program induces an enlargement of the cortical motor
areas targeting the muscles involved in the task, with an
additional decrement of the activation threshold, as meas-
ured by means of TMS. Such map expansions parallel
improvements in motor performance [83]. These results
indicate that the cortex has the potential for rapid and
large-scale functional changes in response to motor skill
learning. One important issue is that an enlargement of a
given neural network occurs at the cost of modifying
another network and therefore with the theoretical risk of
decreasing performance in another task. To date, this the-
oretical concern does not seem to cause any significant
impairments in stroke subjects receiving intensive motor
training.
Evidence for a long-term alteration in brain function asso-
ciated with a therapy-induced motor recovery in neuro-
logical populations has also been provided. For instance,

constraint-induced movement therapy (CIT) can signifi-
cantly change cortical excitability measured by TMS in
both affected and unaffected hemispheres. More specifi-
cally, CIT can result in an enlargement of the motor out-
put map in the affected hemisphere, which is associated
with a greatly improved motor performance of the paretic
limb. A shift on the center of gravity of the output map in
the affected hemisphere was also observed, indicating the
recruitment of adjacent brain areas. Follow-up examina-
tions up to 6 months after treatment showed that motor
performance remained at a high level, whereas the cortical
area sizes in the two hemispheres became almost identi-
cal, representing a return of the balance of excitability
between the two hemispheres toward a normal condition
[84]. These results are in line with PET and fMRI studies in
recovered stroke patients showing that plastic changes tak-
ing place within the ipsilateral, noninfarcted hemisphere
might contribute to the restitution of motor function
[7,85-87]. A recent meta-analysis further underlines the
positive impact of motor rehabilitation for the upper
extremities, showing that practice-dependent recruitment
of the ipsilesional hemisphere induces clear functional
motor gains [88]. Increased engagement of the damaged
hemisphere is expressed by either an increase in the area
of the brain subserving the paretic arm movement, as
shown by brain imaging techniques, and by greater signal
strengths of physiological-functional measures (MEPs)
within the sensorimotor cortex of the lesioned hemi-
sphere [88].
Although motor training can lead to neurofunctional

adaptation within a matter of minutes [89], long-term
representational changes may take days [83] or weeks of
practice [90]. Rapid changes are bound to be reflected in a
less specific remodelling of network activity [91]. Instead,
enduring change is reflected in, for example, augmented
dendritic branching [92] and synaptogenesis [93], possi-
bly provoked by specific gene induction [94,95]. Ulti-
mately these processes result in an increase in the efficacy
of synaptic transmission [96]. In strict analogy with the
NIBS-induced after-effects, NMDA receptor activation and
GABAergic inhibition are likely mechanisms operating in
use-dependent plasticity in the intact human motor cortex
and point to similarities in the mechanisms underlying
this form of plasticity and long-term potentiation (LTP)
[97]. LTP is associated with the proliferation of dendritic
spines [98]. This morphologic change has been even
found in homologous cortex opposite from the site of an
experimental sensorimotor cortical lesion when the unaf-
fected limb works to compensate for the paretic one [99].
This evidence suggests that the synaptic strength of hori-
zontal connections in the motor cortex are modifiable
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and may provide a substrate for altering the topography of
cortical motor maps during physical intervention based
on motor learning.
Combination of NIBS with motor training to enhance
neuroplasticity and behavioural changes
As we have seen, motor learning and NIBS may share sim-
ilar mechanisms of action for inducing neuroplastic

changes in the human cortex. One possible conjecture
then, is that their combination might mutually maximise
their individual effects. Since learning processes are
accompanied by cortical excitability shifts and by changes
of synaptic efficacy and considering that the after-effect of
NIBS is NMDA-receptor dependent, there is a possibility
that cortical excitability changes induced by cortical stim-
ulation could interact with ongoing motor learning proc-
ess, improving learning-related NMDA-receptor
strengthening. It is noteworthy that synaptic plasticity is
bidirectional [100]. The basic idea is that the ongoing
state of the cortex at the time of physical therapy can rein-
force the long-term effects induced by motor practice. If
so, the rationale of coupling NIBS and motor therapy is
that it is possible to enhance or depress the response of a
neural network to a form of stimulation, e.g. motor train-
ing, by previous priming it with a different form of stimu-
lation, e.g. NIBS (and vice versa). Some experimental
studies provide preliminary support to this hypothesis.
Animal studies using direct repetitive electric stimulation
(ES) of the cortex – a technique that mimics rTMS and can
alter cortical excitability as measured by cortical spreading
depression (CSD) [101] have supported the importance
of priming brain activity. CSD is an indicator of cortical
excitability [102] characterised by alterations in cerebro-
cortical ion homeostasis in response to the direct stimula-
tion of brain tissue. The alterations result in a wave of
neuronal excitation propagating through the cortex fol-
lowed by transient inhibition. It has been found that
when active or sham 1 Hz ES was applied to Wistar rats

preconditioned with active, sham or cathodal tDCS, a pat-
tern suggestive of homeostatic mechanisms emerged
[101]: 1 Hz ES that was applied alone or was preceded by
cathodal tDCS, reduced CSD velocity whereas anodal
tDCS followed by 1 Hz ES increased CSD velocity. Home-
ostatic effects have also been found in the effects of tDCS
on paired associative stimulation (PAS) of human motor
cortex [103] or by preconditioning of rTMS with tDCS
[104]. However there is a fundamental difference when
coupling two techniques of neuromodulation vs. cou-
pling neuromodulation techniques with motor training;
the latter might be better as it can focalize the effects to
specific networks. In fact, several studies have explored the
influence of coupling learning tasks with NIBS on motor
and cognitive functions in healthy subjects. In one exam-
ple, TMS synchronously applied to a motor cortex
engaged in a motor learning task was shown to be effec-
tive in enhancing use-dependent plasticity. Healthy vol-
unteers were studied in different sessions: training alone,
training with synchronous application of TMS to the
motor cortex contralateral or ipsilateral to the training
hand, and training with asynchronous TMS. It was found
that the longevity of use-dependent plasticity was signifi-
cantly enhanced only by TMS applied in synchrony to the
cortex contralateral to the training hand [105]. Carey et al.
(2006) have obtained, however, different results: investi-
gation of the effects of motor learning training, consisting
in finger tracking with the right hand, unexpectedly
showed that 1 Hz rTMS interfered transiently with motor
performance when applied ipsilateral to the training hand

but it had no effect when applied contralaterally [106]. In
another tDCS study [107], the excitability of MT+/V5 and
M1 was increased or decreased by anodal or cathodal
tDCS while subjects were learning a visually guided man-
ual tracking task. Accuracy of tracking movements was
increased significantly by anodal stimulation, whereas
cathodal stimulation had no significant effect on visual
learning. Interestingly, the positive effect of anodal tDCS
was restricted to the learning phase, suggesting a highly
specific effect of the stimulation. Similar results were dem-
onstrated for implicit motor learning in healthy human
subjects [108], and in addition a recent study showed the
beneficial effects of anodal tDCS over the posterior part of
the left peri-sylvian area on language learning [109]. One
important conclusion is that the effects are dependent on
the site of stimulation, task and parameters of stimula-
tion, therefore making difficult to generalize conclusions
on these studies and also opening the possibility to
induce detrimental effects when coupling these two inter-
vention methods; therefore, it is critical to study the com-
bination of these techniques before using it in clinical
practice.
Originally, encouraging results have been found in ani-
mal investigations. Seminal experiments in animals have
shown that coupled forced use of the paretic hand with
implanted electrical stimulation to the ipsilesional M1
lead to significant behavioural improvements with large-
scale expansions of the hand representation into areas
previously representing proximal forelimb movements
[80,110]. In a similar way, a recent prospective, rand-

omized, multicenter study showed that in chronic stroke
intensive motor therapy combined with invasive epidural
electrode is associated with a significant improvement in
motor function [111].
Although investigation with NIBS is still at the beginning,
there are some very promising preliminary results. Khedr
et al. (2005) have explored the effects of rTMS in patients
with acute ischemic stroke as an add-on intervention to
standard physical and drug therapies. rTMS was applied
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over the M1 of the stroke hemisphere for 10 days. rTMS
consisted in ten 10-second trains of 3-Hz stimulation with
50 seconds between each train [112]. The motor treat-
ment consisted in the passive limb manipulation, increas-
ing by the end of the first week to more active movements
if patients improved function. Treatment effects were
measured with clinical scales and neurophysiological
measurements – i.e., resting motor threshold (RMT) of
healthy side, and motor evoked potentials (MEPs) of
healthy and hemiplegic sides. On every scale, patients'
motor scores in the active rTMS group had a significant
greater improvement as compared with sham rTMS, lead-
ing to a higher percentage of independent patients and a
higher percentage of patients having only mild disability
by the time of the follow-up assessment, after 10 days
from the end of the treatment. However, no effect was
seen in patients with massive middle cerebral artery inf-
arcts. 14 out of 21 patients in the real rTMS group recov-
ered MEPs; although MEPs tended to improve more in the

real rTMS group, this was not significantly different from
the sham group. In addition, no correlation between clin-
ical recovery and changes in MEP was found [112].
In other clinical trial [113], patients with chronic hemi-
paretic stroke practiced a complex, sequential finger
motor task using their paretic fingers either after receiving
high-frequency (10 Hz, repeated 8 times) or sham rTMS
over the primary motor cortex (M1) of the damaged hem-
isphere. Changes in the behavior and corticomotor excit-
ability before and after the intervention were examined by
measuring the movement accuracy, the movement time,
and the MEP amplitude. The authors found that rTMS
induced a significantly larger increase in the MEP ampli-
tude than sham rTMS; this corticomotor excitability
change was associated with enhanced motor skill acquisi-
tion.
Rather than trying to enhance the cortical excitability of
the damaged motor cortex, Takeuchi et al (2008) explored
the effect of inhibiting the contralesional motor cortex in
chronic patients [114]. Patients were randomly assigned
to receive either a sub-threshold rTMS over the unaffected
hemisphere (1 Hz, 25 minutes) or sham stimulation and
all patients performed a pinching task after stimulation.
Compared with sham stimulation, rTMS induced an
increase in the excitability of the injured motor cortex and
an improvement in acceleration of the affected hand. The
effect of motor training on pinch force was also enhanced
by rTMS. Such improvement was stable at the follow-up
examination, one week after the intervention [114].
Another study [115] assessed the efficacy of low-fre-

quency 1 Hz rTMS combined with voluntary muscle con-
traction (VMC) on corticospinal transmission, muscle
function, and purposeful movement early after stroke.
rTMS consisted of 5 blocks of 200 1-Hz stimuli (using an
interblock interval of 3 minutes), applied to the lesioned
hemisphere. The treatment was given for 8 working days.
The motor training task in this study was VMC – the
paretic elbow was repeatedly flexed/extended for 5 min-
utes. The main finding was that in patients who under-
went the rTMS combined with VMC, motor-evoked
potential frequency increased 14% for biceps and 20% for
triceps; whereas, with Placebo rTMS plus Placebo VMC,
motor-evoked potential frequency decreased 12% for
biceps and 6% for triceps.
Negative findings have also been reported. A recent study
indeed did not prove the usefulness of combing rTMS
stimulation with a standard motor therapy [116]. Here,
chronic stroke patients undergoing ten days of constraint-
induced therapy (CIT) for upper-limb hemiparesis, which
was combined with 20 Hz rTMS (stimulus train duration
of 2 secs, intertrain interval of 28 secs.) or with sham rTMS
of the affected M1. Primary outcome measures to assess
change in upper-extremity function were the Wolf Motor
Function Test (WMFT) [117] and the Motor Activity Log
(MAL)-Amount [118]. Secondary outcome measures
included the MAL-How Well and the Box and Block Test
(BBT) [119] and MEP threshold. The results showed that,
regardless of the rTMS intervention, participants demon-
strated significant gains on the primary outcome measures
and on secondary outcome measures, further supporting

the efficacy of CIT. Indeed, although a significant decrease
in motor threshold for subjects receiving rTMS was found,
which was not observed after sham rTMS, this increase in
the excitability of the motor system did not translate into
a clinically evident outcome. Ceiling effects and outcome
measures might have contributed to these findings.
tDCS is another technique associated with a significant
beneficial effect on motor recovery after stroke. Although
its beneficial effects on motor function have been shown
by several small studies [26,32,43,71,72,120], actually
there are very few clinical trails of the potential adjuvant
of this technique to physical therapy. Yet, tDCS might be
a more suitable tool to enhance the effects of motor train-
ing as it offers several advantages as compared with TMS
in a rehabilitation setting. For instance, whereas rTMS has
to be delivered in a off-line paradigm and it usually pre-
cedes the behavioural intervention, the portable use of
tDCS allow to deliver the cortical stimulation during the
motor training. Moreover, tDCS modulatory effects last
longer as compared to rTMS – for example, 13 minutes of
stimulation changes brain excitability for up to 90 min-
utes [69]. Finally, due to its physiological effect on the
membrane resting potential, tDCS could to be more
appropriate for priming motor neural network for subse-
quent stimulation with tDCS. Hummel et al (2005) have
recently explored the effects of tDCS on skilled motor
functions in chronic stroke patients [121]. Anodal tDCS
Journal of NeuroEngineering and Rehabilitation 2009, 6:8 />Page 8 of 13
(page number not for citation purposes)
was delivered for 20 min to the affected hemisphere dur-

ing the execution of the Jebsen-Taylor Hand Function Test
(JJT), a widely used assessment of functional hand motor
skills. Active anodal tDCS was associated with improve-
ments in motor function of the paretic hand. The magni-
tude of tDCS-induced improvement in JTT was
approximately 11.75% (+/- 3.61%) and persisted for
more than 25 min after the stimulation ended. However,
patients' performance returned to baseline levels after 10
days of the end of stimulation [72]. In another prelimi-
nary report in chronic stroke, anodal tDCS (1.5 mA) was
combined with robot-assisted arm training (AT) [122].
Over six weeks, patients received 30 sessions of 7 min
tDCS integrated into 20 min of AT. Arm function of three
out of ten patients (two of them with a subcortical lesion)
improved significantly, as measured by the Fugl-Meyer
motor score. In the remaining seven patients, all with cor-
tical lesions, arm function changed little. However, this
study lacked an adequate control group and it included a
small number of patients, who were still in the phase of
spontaneous recovery; therefore no definite conclusions
can be made.
Overall, the data discussed above provide some encourag-
ing information supporting the proposal that NIBS might
optimize the effect of standard physical therapy under cer-
tain circumstances. Beyond the obvious need for further
clinical trials to corroborate the validity of this approach,
attention must be directed in understanding the optimal
way to combine motor training with NIBS. Crucially the
next step is to determine the best parameters required to
optimize the conditioning effects of NIBS on motor ther-

apy, as well as the exact temporal window during which
NIBS can be delivered in order to modulate brain plastic-
ity and enhance the effects of the motor training.
How brain stimulation should be used in combination with
motor training – methods of optimizing functional
improvements
Given the limited number of clinical trails that have
assessed the efficacy of combining NIBS with physical
therapy, any prediction of the clinical utility of this
approach remains speculative. Although further investiga-
tions are needed to make any relevant clinical considera-
tion, some reflections can be delineated in order to make
an optimal use of this approach in the near future. So far,
the best option in order to optimize the effects of coupling
NIBS and motor therapy still needs to be explored but it
likely may depend on different factors, as the stages of ill-
ness (e.g. acute versus chronic), the type of motor training,
the site of stimulation, the timing of stimulation in rela-
tion to physical intervention, baseline cortical activity and
the technique of NIBS used. An essential issue to take into
account when applying these NIBS protocols to a dam-
aged human brain is related to the concept of homeostasis
– that is the human's brain ability to regulate changes in
synaptic plasticity as to avoid drastic changes in its func-
tion. Therefore homeostasis is likely to respond defini-
tively and forcefully to artificial and functionally non-
specific changes in network activity such as those proba-
bly induced by NIBS [123]. Homeostatic plasticity (i.e.,
the dependency of the amount and direction of the
obtainable plasticity from the baseline of a neuronal net-

work) is increasingly recognized as regulatory mechanism
for keeping neuronal modifications within a reasonable
physiological range. Homeostasis provides a means for
neurons and circuits to maintain stable functions in the
face of perturbations such as activity-dependent changes
in synapse number or strength [124]. In this regard, recent
experimental works emphasize the importance of homeo-
static plasticity as a means to prevent destabilization of
neuronal networks that could operate in neurorehabilita-
tive settings [124,125]. In particular, as advised by Thick-
broom (2007), the influence of homeostatic mechanisms
cannot be overlooked either during or after NIBS interven-
tions: homeostatic mechanisms could be a crucial factor
in repeat interventions, as are sometimes employed in
NIBS protocols, or for intervention protocols of longer
duration in which they may begin to act during the inter-
vention itself. They could be one of the main factors that
limit the magnitude and duration of post-TMS effects. For
instance, NIBS could evoke compensatory regulatory
mechanisms, which are a part of the process of maintain-
ing normal brain function. On the other hand, activity-
dependent forms of plasticity, even those incorporating
LTP and LTD mechanisms, are inherently unstable due to
positive feedback [123]. Thus, the successful implementa-
tion of NIBS as adjuvant strategy to physical therapy
should rely on an improved understanding of the under-
lying plastic mechanisms and their functional interaction
with activity-induced plasticity. For instance, a challeng-
ing issue is the time of the NIBS intervention relative to
the motor task. As seen above, when combing to a motor

training, so far NIBS has been usually delivered just before
the task. However, functional therapies could in principle
be implemented at different phases in conjunction with a
NIBS intervention. NIBS preceding the motor training
could potentially prime functional networks for the phys-
ical intervention. Instead, NIBS simultaneously applied
during a behavioural intervention might preferentially
interact with the networks selectively recruited by the
ongoing task. Even the application of NIBS after motor
training could be a potential choice; the underlying
rationale of this approach is that, after the modulation
induced by the motor therapy, a further modulation of
cortical excitability might selectively build up the activity-
dependent activation of a given network and promote its
functional stabilization. It is not completely unlikely that
even after excitability has returned to baseline, perhaps
due to homeostatic regulation, NIBS could still be func-
Journal of NeuroEngineering and Rehabilitation 2009, 6:8 />Page 9 of 13
(page number not for citation purposes)
tionally beneficial [123]. Here, NIBS could be influential
for driving longer-term consolidation of new network pat-
terns. The choice of the more suitable time window for
NIBS intervention likely needs careful examination in
order to exclude maladaptive cortical responses, which
could interfere with or even suppress the effects of the
behavioural therapy. For instance, an excitability modula-
tion induced by tDCS during the performance of a motor
task might be best suited to improve motor learning than
tDCS administered prior of learning or motor behaviour
[126,127]. This is because, during tDCS not only NMDA

receptors, but also calcium channels are modulated, while
the after-effects of tDCS are achieved by modifications of
NMDA receptors alone [29]. Since intracellular calcium
concentration is important for LTP induction [128]
enhanced transmembrane calcium conduction, as proba-
bly achieved during anodal tDCS, might improve learning
processes. On the other hand, a pure modulation of syn-
aptic strength prior to learning might compromise per-
formance, due to homeostatic or defocusing effects.
Therefore, administering tDCS during, and not before,
motor learning might be the best strategy to improve the
effects of physical therapy [126].
The parameters of stimulation – such as number of stim-
ulation sessions, frequency, intensity and site of stimula-
tion – need to be taken in consideration. Relative to the
duration of the cortical stimulation, it is worth mention-
ing that NIBS interventions have relatively short-lived
after-effects compared to experimental LTP/LTD or to the
duration needed for any clinically relevant functional
improvement. However, repeated sessions of NIBS may
have cumulative effects; perhaps due to these cumulative
effects, several sessions of NIBS are usually associated with
greater magnitude and duration of behavioural effects
[129]. This has been also reported in clinical trials in
stroke patients, in which stimulation with rTMS for 10
days can indeed induce a long-lasting improvement of
motor behaviour that lasted for 10 days after the end of
stimulation [32,112]; similarly, cathodal tDCS applied
over 5 consecutive days is associated with a cumulative
motor function improvement that lasts up to 2 weeks after

the end of stimulation. However, interesting, this effect is
not observed when sessions are applied weekly instead of
daily [73]. In fact, multiple stimulation sessions are
required in order to induce a significant manipulation in
synaptic efficacy [130]. Thus, future clinical trails need to
take into account that only prolonged and consecutive
sessions of NIBS can translate into a long-lasting func-
tional gains in stroke patients.
Until now physical therapy has been largely combined
with NIBS applied to the motor cortex; nonetheless, other
brain areas might be involved in motor recovery. For
instance, higher levels of contralesional activity in pre-
frontal and parietal cortices appear to be predictive of a
slower motor recovery, suggesting a possible negative role
of activity in these areas of the intact hemisphere in func-
tional restoration [38,131]. If so, suppression of such
activity with NIBS might be a valuable intervention. Thus,
modulation of excitability in areas beyond the primary
motor cortex should be also taken into account as poten-
tially interacting with the damaged motor areas, driving
their activity-dependent activation. In patients with TBI,
given their additional attentional impairments which neg-
atively impact the efficacy of standard motor therapies
[132], a modulation of attentional networks might
enhance the responsiveness to standard motor rehabilita-
tion.
Another controversial issue is related to the side of stimu-
lation. It is still unclear whether it is better to suppress
activity in the undamaged hemisphere or increase activity
in the perilesional cortex. To date only one study, using

tDCS, has directly compared the effectiveness of down-
regulating the contralesional hemisphere with facilitation
of the stroke hemisphere in patients with motor stroke;
both approaches were found to be equally effective, with
slightly greater improvement after suppression of the
intact hemisphere [71]. However this was a small study
and patient selection might have played a significant role.
It is not yet known whether this is also true for rTMS. At
least it appears that application of excitatory rTMS proto-
cols to the stroke hemisphere is safe and does not increase
the risk of provoking a seizure [133]. In any case, it is
likely that rather than a global modulation of one or
another hemisphere, more targeted, focal modulation of
activity in selected cortical regions of each hemisphere
might be desirable. Furthermore, the application of differ-
ent strategies in different phases following the brain insult
might be needed. Finally, it is worth remembering that
currents induced by NIBS in the lesioned brain can be per-
turbed by anatomical changes which can render the neu-
romodualtory effects less predictable [52].
Importantly, the effects of NIBS are also task dependent;
therefore it is possible that some motor tasks are more sus-
ceptible to modulation by NIBS than others. If so, the
choice of the motor training task might be a critical deter-
minant for the success of the therapy.
Overall, if guided by a careful consideration of the under-
lying mechanisms, the combination of NIBS with func-
tional therapies has the potential to drive plastic changes
in brain-damaged patients. This might in turn promote
remarkable clinical gains in motor functions that other-

wise could not be achieved by administering NIBS or
motor treatment alone. Clearly, further investigation is
warranted to address the overall utility of NIBS as an adju-
vant to stroke rehabilitation, and the optimal strategy to
Journal of NeuroEngineering and Rehabilitation 2009, 6:8 />Page 10 of 13
(page number not for citation purposes)
combine the two interventions in order to maximize their
functional interaction.
Conclusion
The uninjured tissue may be particularly receptive to
modulation by various external tools including behavio-
ral training and neuromodulatory approaches such as
noninvasive brain stimulation. Given that both strategies,
motor learning and cortical stimulation, have some simi-
larities in their mechanisms of action, such as both induce
similar changes in the local excitability in the lesioned
and contralesional motor cortical area associated with
long-lasting after-effects, their combination might be
more beneficial than their use alone. In fact, brain stimu-
lation can prime cortical excitability for a subsequent
motor training task therefore optimizing processes of
motor learning involved in standard rehabilitation thera-
pies, leading to more pronounced and longer lasting func-
tional gains. Some preliminary evidence seems to support
this view. However, other studies failed to demonstrate a
significant effect of brain stimulation as an adjuvant to
standard motor therapy. In the future, the successful
implementation of combined NIBS and motor therapy
will critically rely on improved understanding of their
functional interactions and associated effects on neural

plasticity. Greater understanding of the mechanisms of
action of each approach is necessary in order to optimize
their combined use in rehabilitation and realize the prom-
ise of a more effective means to promote functional recov-
ery after brain injury.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
NB, APL and FF conceived the initial idea. NB and FF
wrote the first draft and all authors revised and approved
the final manuscript.
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